What drives performance in molecular MPNNs? An operator-level factorial benchmark

Message-passing neural networks (MPNNs) are widely used for molecular property prediction, but their deployment as monolithic architectures makes it difficult to identify how specific message-passing operators affect performance. We present an operator-level factorial benchmark that decomposes 2D molecular MPNNs into the three families of message-seed initialization, node-edge fusion, and node update operators. The resulting 84 configurations are benchmarked on ten MoleculeNet datasets under a shared experimental setup and statistical analysis protocol. Across this controlled design, performance variation is associated primarily with message construction rather than update complexity. Message-seed initialization shows significant family-level effects for both regression and classification, node-edge fusion shows a significant family-level effect for regression with descriptive advantages for concatenation-based mixing, and the update family shows no statistically supported effect for either endpoint family. A representation probe into the Quinethazone molecule further demonstrates that concatenation-based mixing can better differentiate chemically distinct heteroatoms and withstand oversmoothing than Hadamard gating. Representative configurations selected separately for classification and regression recover competitive performance relative to established molecular graph neural network (GNN) baselines, ranking numerically best on eight of ten benchmark datasets. These empirical results are interpreted through concise mechanistic analyses of representative node-edge fusion and update operators. Our findings provide empirical design heuristics for molecular MPNNs by turning model design from a search over monolithic architectures into a targeted assessment of where and how chemical information enters the message-passing pipeline.

SCALE:Scalable Conditional Atlas-Level Endpoint transport for virtual cell perturbation prediction

Virtual cell models aim to enable in silico experimentation by predicting how cells respond to genetic, chemical, or cytokine perturbations from single-cell measurements. In practice, however, large-scale perturbation prediction remains constrained by three coupled bottlenecks: inefficient training and inference pipelines, unstable modeling in high-dimensional sparse expression space, and evaluation protocols that overemphasize reconstruction-like accuracy while underestimating biological fidelity. In this work we present a specialized large-scale foundation model SCALE for virtual cell perturbation prediction that addresses the above limitations jointly. First, we build a BioNeMo-based training and inference framework that substantially improves data throughput, distributed scalability, and deployment efficiency, yielding 12.51* speedup on pretrain and 1.29* on inference over the prior SOTA pipeline under matched system settings. Second, we formulate perturbation prediction as conditional transport and implement it with a set-aware flow architecture that couples LLaMA-based cellular encoding with endpoint-oriented supervision. This design yields more stable training and stronger recovery of perturbation effects. Third, we evaluate the model on Tahoe-100M using a rigorous cell-level protocol centered on biologically meaningful metrics rather than reconstruction alone. On this benchmark, our model improves PDCorr by 12.02% and DE Overlap by 10.66% over STATE. Together, these results suggest that advancing virtual cells requires not only better generative objectives, but also the co-design of scalable infrastructure, stable transport modeling, and biologically faithful evaluation.